A four-year study is proposed to investigate (1) the relationship between fluphenazine (FPZ) blood levels and efficacy in the treatment of acute schizophrenic exacerbations, and (2) the pharmacokinetics of oral FPZ and of FPZ decanoate. The small concentrations of FPZ found during treatment (often less than 1 ng/ml) have hindered study of blood levels, but more specific and sensitive assay techniques are now available. Pilot data presented here suggest that there may be a minimum effective blood level of FPZ for most patients during oral treatment. The establishment of a therapeutic blood level range would be useful for the regulation of dosage for individual patients, and for the study of neuroleptic responsiveness as biological variable. (1) Sixty RDC schizophrenic and schizoaffective (mainly schizophrenic subtype) patient with active psychotic symptoms will be treated with 10, 20 or 30 mg of fluphenazine HC1 p.o. daily for 28 days, under randomized, double-blind conditions, after a drug-free period. Bloodlevels and clinical ratings at baseline, 4, 7, 14, 21 and 28 days will permit study of relationships among blood levels, clinical variables and adverse effects. Blood levels and clinical assessments at 4 and 24 hours after the initial 5 mg dose will permit study of the prediction of steady state level from early levels, and of subjective response in relation to outcome. Neuroleptic resonse, positive/negative symptoms, CAT, neuropsychological and electrophysiological measures, premorbid and follow-up data will be examined wiht data from this and associated studies. (2) Blood level/efficacy relationships during treatment with FPZ decanoate deserve investigation, but data presented here suggest that FPZ levels may continue to rise for longer periods after initiation of treatment, and persist for longer periods, than has been generally appreciated. Without more data, sampling points cannot be selected for long-term clinical studies. Therefore, 25 schizophrenic patients starting FPZ decanoate at randomized, fixed doses (12.5 or 25 mg every 2 weeks) will be monitored with blood levels prior to each injection, to obtain 10 or more who have completed 1 year of consecutive injections and 4 months of blood levels after discontinuation of drug. Accumulation and disappearance will be studied.